Despite the clinical success of targeted therapies directed towards driver oncogenes in many cancers, resistance to these therapies often emerges quickly, culminating in poor clinical outcomes. Although emerging evidence has revealed the crucial role of lineage plasticity in driving therapy resistance, the exact molecular mechanism and kinetics of acquiring lineage plasticity is not clearly understood. More importantly, therapeutic approaches targeting lineage plasticity-driven resistance are not currently available, underlying the unmet clinical urgency to identify druggable targets which drive lineage plasticity and resistance.
Our goal is to identify the underlying molecular mechanisms driving lineage plasticity and therapy resistance in various cancers. Through a multi-disciplinary approach integrating 3D organoid modeling, bulk and single cell RNA-Seq (scRNA-Seq) analysis, we illuminate the once hidden intratumoral heterogeneous subclones, which express multilineage, stem-like, and lineage plastic transcriptional programs, as the driving force of AR therapy resistance. Revealing the molecular mechanisms driving lineage plasticity and resistance would by the key steps towards novel approaches for clinical intervention to overcome resistance and benefit patients.
The Two Faces of Cancers: Janus Kinase Enables Lineage Switch. This story is published in Nature Cancer 2022.